Acute lung injury and chronic lung disease are together the third leading cause of death in the United States. This is due to the lack of effective therapis and a poor understanding of the mechanisms driving the pathology of these disorders. The major objective of this PPG is to advance novel therapies for the treatment of acute and chronic lung disease. Adenosine is produced following tissue injury, particularly injury involving ischemia and hypoxia. The production of extracellular adenosine and its subsequent signaling through adenosine receptors plays an important role in orchestrating injury responses in multiple organs including th lung. This process of regulated adenosine production and signaling following injury is known as the hypoxic adenosine response. Our research efforts have established that this response plays an important role in orchestrating injury responses in the lung, but through mechanisms that are not well understood. Activation of this pathway can attenuate acute lung injury, while blockade of this pathway is beneficial on aspects of chronic lung disease. We need to better understand how the hypoxic adenosine response is regulated in different types of lung injury in order to know when and how to target the activation or inactivation of this pathway. This will be done by examining direct injury processes in the lung as well as common secondary pulmonary injuries such as those seen associated with sickle cell disease and acute kidney injury. This will allow us to understand important aspects of systemic and organ responses critical to eventual human therapies. We will capitalize on our recent data showing that the regulation of the equilibrative nucleoside transportrs (ENTs) is a novel mechanism for regulating extracellular adenosine following injury. We will conduc mechanistic analysis in novel mouse models, including cell-specific knockouts of ENTs and other components of the hypoxic adenosine response. Importantly, we will also conduct rigorous assessment of the hypoxic adenosine response in disease relevant tissues from patients with acute and chronic lung disease as well as patients with sickle cell disease and kidney injury that can develop pulmonary complications. This approach will help advance emerging adenosine-based therapies forward for the treatment of lung disease. Three Component Projects, Two Scientific Cores and an Administrative Core are planned to facilitate the research goals and interactions of this PPG.